Project Summary: Tobacco and alcohol are the most frequently used and co-abused drugs, with smokers being ten times more likely to develop alcohol-related disorders. Despite the consistent positive correlation between smoking and subsequent alcohol abuse, the physiology that underlies the interaction between tobacco and alcohol use remains remarkably under studied. Individuals disposed to alcohol abuse often exhibit less sensitivity and less intoxication after moderate alcohol drinking. Based on dopamine's crucial role in drug reinforcement, it has been hypothesized that individual differences in dopamine signaling contribute to variations in alcohol sensitivity. Our preliminary data show that pre-exposure to nicotine decreases the dopamine response arising from alcohol (i.e., lower sensitivity). Correlated with the smaller alcohol-induced dopamine signals, acute pre- exposure to nicotine increases alcohol self-administration. The literature and our preliminary results led us to the following working hypothesis: exposure to nicotine at a concentration obtained from tobacco decreases the responsiveness of the mesolimbic dopamine system to alcohol and increases the vulnerability to alcohol abuse. We will measure the consequences of nicotine pre-exposure on alcohol-induced dopamine responses, particularly during alcohol self-administration. We use a powerful array of in vivo and in vitro techniques to measure the consequences of nicotine pre-exposure upon the dopamine system during non-contingent alcohol administration and during operant alcohol self-administration. After nicotine pretreatment, we measure the responsiveness of the mesolimbic system, including dopamine neuron activity, dopamine release, and dopamine re-uptake. We also examine the underlying cellular and synaptic events. The methodology includes in vivo microdialysis and multi-tetrode unit recordings during alcohol self-administration. In that way, midbrain neural activity and dopamine signaling are being precisely linked to the complete repertoire of behaviors during alcohol self-administration. To obtain greater experimental control, brain slices are cut from those same neural areas to investigate synaptic level mechanisms. The proposed studies cross neural levels of integration, from synaptic and cellular to systems and behavior, providing novel kinds of data that have not previously been obtained during the biologically relevant protocol of alcohol self-administration. Understanding the neural circuits and the mechanisms that drive those circuits will provide a valuable foundation for developing strategies that diminish the propensity for alcohol abuse caused by smoking. The aim is to examine the circuit elements and their interactions as freely-moving rats self-administer alcohol. Upon completing this study, this highly relevant animal model (monitored with our powerful array of techniques) will serve as an ideal testing platform to understand how therapeutic interventions influence the circuitry that drives alcohol abuse. Future therapeutic strategies can be rationally developed and tested based on biological processes that underlie nicotine's influence upon alcohol use.